Department of Organic Chemistry, Faculty of Science , Palacký University , 17 listopadu 12 , 771 46 Olomouc , Czech Republic.
Department of Chemistry and Biochemistry , University of Notre Dame , 251 Nieuwland Science Center , Notre Dame , Indiana 46556 , United States.
ACS Comb Sci. 2019 Jan 14;21(1):1-5. doi: 10.1021/acscombsci.8b00145. Epub 2018 Dec 20.
We present the solid-phase synthesis of 1,2-dihydroquinazoline-2-carboxylate derivatives with a quaternary carbon in position 2 and their subsequent cyclization in solution into compounds with unique 3D architectures and pharmacological relevance-spiroquinazolines, namely, 1' H-spiro[pyrrolidine-3,2'-quinazolin]-2-ones and 1' H-spiro[piperidine-3,2'-quinazolin]-2-ones. Acyclic precursors were prepared from commercially available building blocks: protected amino acids (2,4-diaminobutyric acid and ornithine), 2-nitrobenzensulfonyl chlorides and α-bromoacetophenones. The crucial step of the synthesis was a base-mediated tandem reaction including C-arylation followed by cyclization into indazole oxides, and the formation of a 5-membered heterocycle was accomplished by ring expansion into quinazolines. These derivatives were cyclized into spiro compounds in solution after cleavage from the resin.
我们提出了 1,2-二氢喹唑啉-2-羧酸酯衍生物的固相合成，其在 2 位具有季碳原子，并且随后在溶液中环化生成具有独特 3D 结构和药理学相关性的螺环喹唑啉，即 1' H-螺[吡咯烷-3,2'-喹唑啉]-2-酮和 1' H-螺[哌啶-3,2'-喹唑啉]-2-酮。无环前体可从市售的构建块制备得到：保护的氨基酸（2,4-二氨基丁酸和鸟氨酸）、2-硝基苯磺酰氯和α-溴代苯乙酮。合成的关键步骤是一个碱介导的串联反应，包括 C-芳基化，随后环化生成吲唑氧化物，并且通过扩环到喹唑啉中形成五元杂环。这些衍生物在从树脂中裂解后在溶液中进行环化生成螺环化合物。
